Back to basics

LA JOLLA, Calif.–– An international team led by scientistsfrom the Scripps Research Institute, the Swiss Tropical Institute, the GenomicsInstitute of the Novartis Research Foundation (GNF) and the Novartis Institutefor Tropical Diseases has discovered a drug candidate that represents apotentially new class of drugs to treat malaria.

According to one of the leadresearchers, this drug candidate was advanced as the result of a simplecell-based screening process, rather than more advanced medical researchmeasures.Clinical trials for the compound are planned for later thisyear.

"We're very excited by the new compound," says ElizabethWinzeler, a Scripps Research associate professor and member of the GNF. "It hasa lot of encouraging features as a drug candidate, including an attractivesafety profile and potential treatment in a single oral dose."

Winzeler says this is her first experience with developing apromising drug candidate. She also indicated that the simple scientific methodused in the research—a classic evolution study of generations of genes—wasemployed to drill down into the action of a specific compound within a parasitecell.

Rather than be closer to a cure after a century of worktoward its eradication, the parasitic affliction malaria seems to be diggingin. It is transmitted through infected mosquitoes that inject upon their bitesthe Plasmodium parasite. Malaria isendemic in some of the poorest parts of the world, including large swaths ofthe African continent, and the disease disproportionately impacts children andpregnant women.

Conversely, the need for new treatments is great, but littleeconomic incentive exists to find one.

According to Winzeler, this disparity became more pronouncedin the 1990s, when chloroquine lost its efficacy as an antimalarial, and thecorresponding result was an explosion of malaria cases is Africa.

Winzeler has been pondering this problem for many years, andfirst began on the path to this recent development about seven years ago. Aftersome initial slow progress, she and her team of scientists decided to pursuecell-based screening, a basic, tried-and-true approach in the development ofnew therapies.

She says a partnership with Novartis evolved in 2005, and in2006, the research received support from Medicines for Malaria Venture and theWellcome Trust.

After developing and using a high-throughput screen toidentify compounds active against the malaria parasite Plasmodium falciparum, Novartis offered its extensive library of purifiednatural products. Winzeler led the research process with Thierry Diagana of theNovartis Institute of Tropical Diseases.

From the first screen, which turned up 275 compounds withanti-malarial activity, down to the final pass, which left 17 compounds in therunning, Winzeler and her team were looking for a class of chemicals perhapsoverlooked before.

The research involved labs in San Diego and Singapore, amongothers.

One compound stood apart from the small pack.Spiroindolones, a chemical in a class of molecules that had never been soughtafter for anti-malarial punch, looked like it held promise.

Additional work wasdone to make and study spiroindolone derivatives to find the safest andstrongest candidates. After additional testing at the Swiss Tropical and PublicHealth Institute, NITD609 crossed the finish line as the most likely to succeedin trials.

Winzeler, who says she was more interested in looking atdrug resistance as opposed to looking for targets, decided that she would lookfor single-base changes in drug-exposed genomes.

This method, she says,diffuses the traditional criticism of the chemistry community that research isflying blind in not knowing what target is being sought first.

As is more eloquently described by the researchers in anarticle in the Sept. 3 issue of Science,an experiment was conducted in which Winzeler's GNF colleague Case McNamaracloned a Plasmodium falciparumparasite and cultured each separately: one in a regular culture, and anotherwith a small amount of the potential drug candidate.

The NITD609-spiked culture, over time, hosted parasites thatbegan to demonstrate drug resistance. And when the researchers further examinedthe many generations of the two groups of organisms, only a few geneticmutations were observed.

The end result was the identification of one gene, PfATP4 asa target. The protein PfATP4 could then be the target, or could be part of thepuzzle in another way.

"We haven't done the definitive experiment to identifyPfATP4 as the target yet. PfATP4 is indicated by what we now know—that it mightwork," Winzeler explains. "It's a class of targets that makes sense."

The Scripps Research Institute is one of the world's largestindependent, nonprofit biomedical research organizations and seeks to utilizebasic biomedical science to comprehend the most fundamental processes of life.

Scripps Research is internationally recognized for its discoveries inimmunology, molecular and cellular biology, chemistry, neurosciences,autoimmune, cardiovascular and infectious diseases and synthetic vaccinedevelopment. It was established in its current configuration in 1961 andemploys approximately 3,000.